Is UNC13D p.Arg102Gln (c.305G>A) pathogenic?

UNC13D p.Arg102Gln (c.305G>A) is classified Uncertain significance in UNC13D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-16). AlphaMissense: likely benign (0.0659); Very rare (popmax 0.00334%, amr); Associated with familial hemophagocytic lymphohistiocytosis 3.

What condition is associated with UNC13D p.Arg102Gln (c.305G>A)?

UNC13D p.Arg102Gln (c.305G>A) is associated with familial hemophagocytic lymphohistiocytosis 3 (ClinVar).

How common is UNC13D p.Arg102Gln (c.305G>A) in the general population?

UNC13D p.Arg102Gln (c.305G>A) is very rare (popmax 0.00334%, amr) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about UNC13D p.Arg102Gln (c.305G>A)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

UNC13D p.Arg102Gln

c.305G>A · rs778208597 · VCV1393697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hemophagocytic lymphohistiocytosis 3

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.85	donor gain · deltas
Pangolin	Δ0.57	gain · loss 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -2.2
Regional constraint	o/e 0.90	unconstrained · MANE · 7,978 bp · p 0.017 · regional, not allelic
Overall
CADD	16.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,836 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000497% 8/1,608,284 alleles · very rare exomes 7/1,456,934 · genomes 1/151,350 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,918
East Asian	0.00225%	44,490
South Asian	0.0022%	45,490
European (non-Finnish)	0.000255%	392,682

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: UNC13D
Protein: p.Arg102Gln
Coding: c.305G>A
MANE Select: NM_199242
dbSNP: rs778208597
Type: single nucleotide variant
Location: chr17:75843030 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 102: the c2 1 domain

Full UNC13D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hemophagocytic lymphohistiocytosis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

UNC13D p.Arg102Trp Uncertain significance ★★ ⚠ same residue
UNC13D p.Arg102Pro Uncertain significance ★ ⚠ same residue
UNC13D c.1055+1G>A Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.118-307G>A Pathogenic ★★ same condition
UNC13D c.118-308C>T Pathogenic/Likely pathogenic ★★ same condition
UNC13D c.1389+1G>A Pathogenic ★★ same condition
UNC13D c.1596+1G>C Pathogenic ★★ same condition
UNC13D c.1727+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/unc13d-p-arg102gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown